Recently, beta-lactam antibiotics having a beta-lactam ring in their structurs as in penicillin derivaties have been discovered in the natural world. As the typical example thereof, thienamycin having the following structural formula was first isolated by fermentation of microorganism Streptomyces cattleya (Journal of American. Assoc. Vol. 100, p6491, 1978). ##STR1##
Thienamycin=[5R-[5.alpha., 6.alpha.(R*)]]-3-[(2-aminoethyl)thio-]6-(1-hydroxyethyl)-7-oxo-1-azabicycl o[3.2.0]hept-2-ene-2-carboxylic acid
According to the result of antimicrobial activity test, it has been identified that thienamycin exhibits a broad and potent antimicrobial activity against gram-positive and gram-negative bacteria. Thus, thienamycin was expected as a beta-lactam antibiotic substance having a high clinical utility. However, it has been reported that since thienamycin itself is chemically unstable and can be readily decomposed in vivo by dehydrogenase-1(DHP-I enzyme) present in kidney, when thienamycin is clinically administered, antibacterial activity in vivo exhibits a tendency to reduce and the recovery rate in urine is extremely low (Antimicro. Agent. Chemother. Vol 22, p62, 1982). Thus, in order to prepare the compound having an improved chemical stability while maintaining a good antibacterial activity of thienamycin numerous thienamycin derivatives have been synthesized. Among such thienamycin derivatives, particularly imipenem, i.e. (5R, 6S, 8R)-3-[[2-(formimidoylamino)ethyl]thio]-6-(1-hydroxyethyl)-7-oxo-1-azabicy clo[3.2.0]hept-ene-2-carboxylic acid hydrate which is prepared by formylating an amino group in thienamycin, exhibits antibacterial activity equivalent to, or higher than, that of thienamycin against various bacteria including beta-lactamase producing strains and particularly a potent antibacterial activity against Pseudomonas aeruginosa, which is 2 to 4 times stronger than that of thienamycin and further shows a slightly improved stability in a solution in comparison withy thienamycin. Accordingly, imipenem was developed as a pharmaceutical medicament which can be practically and clinically utilized (J. Med. Chem. Vol. 22, p1435, 1979). However, since imipenem can be readily decomposed by DHP-I enzyme present in human kidney as like as thienamycin, it cannot be used for treatment of urinary tract infection and further, substances produced by DHP-I enzyme decomposition can induce a serious renal toxicity. Accordingly, imipenem cannot be administered alone and should be administered together with DHP-I enzyme inhibitors such as cilastatin (J. Antimicrob. Chemo. Vol. 12 (Suppl. D) pl(1983)). Moreover, recently a frequent use of imipenem for prophylaxis and treatment of infectious diseases results in remarkable increase of imipenem-resistant Straphylococcus aureus and Pseudomonas aeruginosa strains in clinical field. Imipenem cannot provide a suitable therapeutic effect on diseases caused by such resistant strains.
As a result of an effort to solve such disadvantages, many antibiotics having chemical structure and pharmacological activity similar to imipenem but not having the above-mentioned disadvantages involved in imipenem have been developed. For example, they are disclosed in European Patent No. 411664A, 272456, 272457, 280771, 341557 and the like. Among these patent specifications, European Patent No. 411664A discloses a carbapenem Compound having 2-[2-(aminocarbonyl)vinyl]pyrroldin-4-yl]-thio group at 2-position of a carbapenem basic structure with a specific example of (1R, 5S, 6S)-2-[(2S, 4S)-2-[(E)-2-(aminocarbonyl)vinyl]-pyrrolidin-4-yl-thio]-6-[(R)-1-hydroxye thyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid (Bo-2171, compound of Example 3). Such beta-lactam antibiotics generally exhibit a toxic effect selectively only on pathogenic bacteria with substantially no toxic effect on animal cells. Accordingly, they have been broadly and safely used for treatment of infectious diseases caused by bacteria for clinical purpose. However, since these beta-lactam antibiotics do not sufficiently exhibit a satisfactory antibacterial effect on causative microorganisms for incurable infectious disease, such as Staphylococcus aureus and Pseudomonas aeruginosa which are resistant to methicillin, their clinical use is greatly restricted, particularly in immunodeficient patients from which such resistant strains are frequently isolated. Further, although such known antibiotic compounds have a resistance to DHP-I enzyme to some extent, it is not sufficient to the desired extent. Accordingly, the development of antibiotic compounds showing an improved antibacterial activity against such resistant strains has been continuously required. Specifically, the major aspect of development of a novel carbapenem antibiotic compound resides in an increase of resistance against DHP-I enzyme and a reduction of renal toxicity and side effects on central nervous system as well as an increase of antibacterial activity.